Glatiramer acetate is one of the important drugs for the treatment of Remitting and Relapsing form of Multiple Sclerosis (RRMS). It belongs to a unique chemical class of compounds known as polypeptides or peptide polymers. Glatiramer acetate is also known as copolymer-1. It is a copolymer comprising of four naturally occurring amino acids namely L-glutamic acid, L-alanine, L-tyrosine and L-lysine with an approximate average molar fraction of 0.141, 0.427, 0.095 and 0.338 and an average molecular weight of 5000-9000 daltons.
The process for preparation of glatiramer acetate is described in Euro. J. Immune. 1, 242 (1971) [Tietelbaum et al.], U.S. Pat. No. 3,849,550 [Tietelbaum, et al.]. In these publications, the process reported consists of polymerizing N-carboxyanhydrides of tyrosine, alanine, γ-benzyl glutamate and ε-N-trifluoroacetyllysine in dioxane with diethylamine as initiator to afford protected copolymer-1. The deblocking of γ-carboxyl group of glutamic acid in the protected copolymer-1 is affected by hydrogen bromide in acetic acid to yield trifluoroacetyl copolymer-1. Removal of trifluoroacetyl group of lysine from trifluoroacetyl copolymer-1 by aqueous piperidine, followed by dialysis yields copolymer-1 (glatiramer acetate). In addition U.S. Pat. No. 5,800,808; U.S. Pat. No. 5,981,589; U.S. Pat. No. 6,048,898; U.S. Pat. No. 6,054,430; U.S. Pat. No. 6,342,476; U.S. Pat. No. 6,362,161 and WO 00/05250, also describe essentially the same method for preparation of glatiramer acetate. These patents elaborate on the process indicated in the earlier patents cited above, like specifying the debenzylation reaction time of protected copolymer-1. As per these patents, the debenzylation reaction is carried out for 10-50 h at 20-28° C. to achieve the molecular weight of 5000-9000 daltons for glatiramer acetate.
Indian patent IP 190759 claims the method of manufacturing of copolymer-1. This patent also claims as in the above cited US patents the conditions for the debenzylation step. The debenzylation reaction is carried out for 10-50 h at 20-28° C. to achieve the desired molecular weight of 5000-9000 daltons for glatiramer acetate.
The debenzylation reaction with hydrogen bromide in acetic acid is hazardous on account of release of hydrogen bromide fumes. In addition, benzyl bromide is generated as reaction by-product. The released benzyl bromide is a highly reactive electrophile and reacts with nucleophiles like primary and secondary amines to generate unwanted N-alkylated products. Also, it is highly lachrymatory and handling it in large quantities on commercial scale is hazardous and unsafe. None of the above patents provide a method for removing benzyl bromide impurity from the reaction mixtures. The present invention describes debenzylation reaction of protected copolymer-1 for shorter duration of time at a higher temperature and a method to remove benzyl bromide from the reaction mixture.
According to WO 2004/043995, glatiramer acetate is prepared employing building blocks N-carboxyanhydrides of L-,γ-benzyl glutamate, ε-N-benzyllysine, alanine, and tyrosine. In this patent the benzyl protecting groups are deblocked by palladium carbon in a single stage. In the US patent 2006/00172942 A1, benzyl deprotection by hydrogenolysis is described. Both these methods use building blocks those are difficult to prepare and are not available in commercial quantities.